Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among older adults with ~16,000 people being diagnosed with this disease each year in the US. The overall survival of CLL patients varies remarkably from less than 1 year to more than 20 years. Although the Rai/Binet staging systems have been used to guide disease management, stage alone cannot discriminate stable or progressive forms of the disease. This limitation is particularly notable since 70% of all CLL patients are initially diagnosed with early stage (Rai 0/I) and are not treated until they become symptomatic. A number of stage-independent prognostic factors have been identified and include the mutation status of the CLL B cell immunoglobulin heavy chain variable region gene (mutated [M] or unmutated [UM] IGHV), specific cytogenetic abnormalities, and expression of ZAP-70, CD38, and CD49d proteins. Despite adjusting for these factors, accurate prediction of which early stage CLL patients will experience an aggressive clinical course remains challenging. Thus, variability in clinical outcome remains even after grouping patients on the basis of one or more specific prognostic factors. The overall hypothesis of this proposal is that accurate identificatio of early stage CLL patients at highest risk of progression also requires an understanding of the biological role of regulatory noncoding RNAs (ncRNAs) in CLL B cells. It is now known that ncRNAs play a variety of roles in the post- transcriptional regulation of protein-coding gene expression. A relatively new and understudied type of ncRNAs are long noncoding RNAs (lncRNAs), which are defined as RNA transcripts >200 nucleotides in length without evident protein coding function. Greater than 30,000 lncRNA transcripts have been identified thus far in the human genome and there is an emerging and exciting literature demonstrating the diagnostic, prognostic, and therapeutic potential of specific lncRNA genes in various cancers. We believe that accurate identification of early stage CLL patients at highest risk of early progression will not occur until we have factored in the regulatory lncRNA landscape and identify the molecular pathways targeted by CLL specific lncRNAs. In this proposal, we will focus specifically on lncRNA expression in early stage CLL patients with UM IGHV status to ensure adequate statistical power to discover progression-associated lncRNAs. Although UM IGHV status is an overall unfavorable prognostic factor, a significant number of early stage UM IGHV patients do not progress rapidly to require early treatment and the underlying mechanisms of differential clinical outcome within this group of patients remain perplexing. To our knowledge, a comprehensive analysis of lncRNA expression in the context of a well-defined cohort of CLL patients with clinical outcome data and known prognostic factor status has not yet been done. Aim 1 seeks to define lncRNA signatures in progressive vs. indolent early stage IGHV UM CLL patients and identify specific lncRNAs that can predict progression. Aim 2 will assess the biologic activity of candidate lncRNAs associated with variable clinical outcome in this subgroup of CLL patients.